Drug delivery devices and methods

ABSTRACT

This disclosure relates generally to methods and devices for use in treating eye conditions with implantable drug delivery devices. One method includes introducing an implant into the suprachoroidal space, wherein the interior volume of the implant is plugged with a drug-release material comprising at least one active agent that elutes through at least one opening in the implant, wherein the drug-release material degrades from the interior volume of the implant over a period time.

REFERENCE TO PRIORITY DOCUMENT

This application is a continuation of U.S. patent application Ser. No.12/973,853, entitled “Drug Delivery Devices and Methods” by Thomas A.Silvestrini, Tsontcho Ianchulev and Steven John, filed Dec. 20, 2010,which in turn claims priority to U.S. Provisional Patent ApplicationSer. No. 61/289,948, filed Dec. 23, 2009, and entitled “Drug DeliveryDevices and Methods.” The priority of the filing date of Dec. 23, 2009is hereby claimed, and the disclosures of each of the abovementionedpatent applications are hereby incorporated by reference in theirentirety.

BACKGROUND

This disclosure relates generally to methods and devices for use intreating eye conditions with implantable drug delivery devices. Themechanisms that cause glaucoma are not completely known. It is knownthat glaucoma results in abnormally high pressure in the eye, whichleads to optic nerve damage. Over time, the increased pressure can causedamage to the optic nerve, which can lead to blindness. Treatmentstrategies have focused on keeping the intraocular pressure down inorder to preserve as much vision as possible over the remainder of thepatient's life.

Unfortunately, drug treatments and surgical treatments available stillneed much improvement, as they can cause adverse side effects and oftenfail to adequately control intraocular pressure.

SUMMARY

T The subject matter described herein provides many advantages. Forexample, the current subject matter includes improved devices andmethods for the treatment of eye diseases, such as glaucoma, that arelow profile, simple and use minimally-invasive delivery procedures.

Disclosed herein are devices and methods for delivering to a location inthe eye a therapeutic agent to treat an eye condition. In one aspect,the device includes a filamentous body including a shape memory materialand a drug delivery polymer impregnated with the therapeutic agentadapted to elute the therapeutic agent over time. The filamentous bodychanges from a first shape that is relatively straight to a second shapethat is coiled upon release from an implantation device into the eye.The location can include a supraciliary space location, a suprachoroidalspace location or a location near the back of the eye. The coiled secondshape can be cupped to hug a curve of the eye. The shape memory materialcan include a polymer and a shape memory metal alloy.

In one aspect, disclosed is a method of treating an ocular disorder ofan eye including forming a self-sealing incision in the cornea of theeye into the anterior chamber; introducing through the incision animplant including a proximal end, a distal end, and an interior volumein fluid communication with at least one opening. The interior volume isplugged with a drug-release material comprising at least one activeagent. The method also includes passing the distal end and the proximalend of the implant through the anterior chamber; positioning the distalend of the implant into the suprachoroidal space; and eluting the atleast one active agent from the drug-release material through the atleast one opening to treat the eye. The drug-release material degradesfrom the interior volume of the implant over a period of at least 12hours.

In another aspect, disclosed is a method of treating an ocular disorderof an eye including forming a self-sealing incision in the cornea intothe anterior chamber of the eye; introducing through the incision animplant including a proximal end with at least one inflow port, a distalend with at least one outflow port, and an interior volume extendingthrough the implant between the at least one inflow port and at leastone outflow port. The implant is mounted on a delivery wire of animplantation instrument extending through the interior volume of theimplant. The method also includes passing the distal end and theproximal end of the implant through the anterior chamber; positioningthe distal end of the implant into the suprachoroidal space using theimplantation instrument; and flowing a drug-release material having atleast one active agent through the delivery wire of the implantationinstrument and the interior volume of the implant.

In another aspect, disclosed is a device for delivering to an eye atherapeutic agent to treat an eye condition that includes an elongate,filamentous body having a proximal end and a distal end and a polymermatrix impregnated with the therapeutic agent that is adapted to elutethe therapeutic agent into the eye over time. The proximal end isadapted for at least partial placement in a first location of the eyeand the distal end is adapted to extend to a second location within theeye. The first location can include a supraciliary space location or asuprachoroidal space location. The second location can include alocation near the back of the eye. The elongate, filamentous body canfurther include an anchor coupled near the proximal end that is adaptedto anchor the filamentous body within the eye. The elongate, filamentousbody can also include a grasping element coupled near the proximal endand extending into a region of the anterior chamber.

In another aspect, disclosed is a method of delivering to the eye atherapeutic agent to treat an eye condition. The method includes loadingan implantation device with one or more bodies of drug delivery polymerimpregnated with the therapeutic agent and adapted to elute thetherapeutic agent over time. The method also includes forming anincision in the cornea of the eye; passing the implantation devicethrough the incision into the eye along a pathway through the anteriorchamber and into at least a portion of the supraciliary space;implanting the one or more bodies with the implantation device into alocation in the eye; and eluting the therapeutic agent from the one ormore bodies.

The one or more bodies can include pellets, beads, particles, gels,nanotubes, and fibers. The one or more bodies can be implanted in asingle location within the eye using the implantation device. At leastone of the one or more bodies can be formulated to include at least twodrug delivery zones each adapted to elute the therapeutic agent overtime. The at least two drug delivery zones can elute a singletherapeutic agent or at least two therapeutic agents. The two or morebodies can be implanted in at least one location within the eye during asingle application using the implantation device. The two or more bodiescan be impregnated with a single therapeutic agent or with more than onetherapeutic agent. The location can include the supraciliary space, thesuprachoroidal space or a location near the back of the eye.

In another aspect, disclosed is a method of delivering to the eye atherapeutic agent to treat an eye condition including loading animplantation device with a filamentous body including a shape memorymaterial and a drug delivery polymer impregnated with the therapeuticagent adapted to elute the therapeutic agent over time; forming anincision in the cornea of the eye; passing the implantation devicethrough the incision into the eye along a pathway through the anteriorchamber and into at least a portion of the supraciliary space;implanting the filamentous body with the implantation device into alocation in the eye such that the filamentous body changes from a firstshape to a second shape upon release from the implantation device intothe eye, wherein the first shape is relatively straight and the secondshape is coiled; and eluting the therapeutic agent from the filamentousbody into the eye. The location can include a supraciliary spacelocation, a suprachoroidal space location or a location near the back ofthe eye. The coiled second shape can be cupped to hug a curve of theeye.

More details of the devices, systems and methods are set forth in theaccompanying drawings and the description below. Other features andadvantages will be apparent from the description and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects will now be described in detail with referenceto the following drawings. Generally speaking the figures are not toscale in absolute terms or comparatively but are intended to beillustrative. Also, relative placement of features and elements may bemodified for the purpose of illustrative clarity

FIG. 1 is a cross-sectional, perspective view of a portion of the eyeshowing the anterior and posterior chambers of the eye;

FIG. 2 is a cross-sectional view of a human eye;

FIGS. 3A-3B show embodiments of drug delivery devices being used totreat a condition of the eye;

FIG. 4A shows an embodiment of a drug delivery device having shapememory in a delivery conformation;

FIGS. 4B-4D show top, side and perspective views, respectively of thedrug delivery device of FIG. 4A in an implantation conformation;

FIGS. 5A-5B show an embodiment of an implant filled with a drug-releasematerial;

FIG. 6A-6D show variations of a delivery tool for delivering animplant(s) into the eye.

FIG. 7 shows a delivery tool being used to deliver an implant into theeye.

FIG. 8 shows another embodiment of an implantation system for deliveryof an implant;

FIGS. 9A-9D shows the implantation system of FIG. 9 filing an implantwith a flowable material upon delivery in the eye;

FIG. 10 shows a schematic view of distal deposition of a flowablematerial near a distal end of an implant;

FIG. 11 shows a schematic view of a cross-sectional view of the eyehaving an implant and a distal deposition creating a lake within thesurrounding tissues.

DETAILED DESCRIPTION

Described herein are devices, systems and methods for the treatment ofeye diseases such as glaucoma, macular degeneration, retinal disease,proliferative vitreoretinopathy, diabetic retinopathy, uveitis,keratitis, cytomegalovirus retinitis, cystoid macular edema, herpessimplex viral and adenoviral infections and other eye diseases. Thedevices described herein can deliver therapeutics to select regions andstructures. The devices described herein can deliver therapeutics in atime-release fashion within the eye. The devices described herein caninclude memory devices that change shape upon implantation as will bedescribed in more detail below. The implants described herein caninclude a drug-release material such as a biodegradable polymerimpregnated with a drug, wherein the drug can be delivered in atime-release fashion and used for disease treatment such as reduction ofaqueous production or improved outflow of aqueous through uveoscleralstructures or the treatment of other eye disorders

Anatomy of the Eye

FIG. 1 is a cross-sectional, perspective view of a portion of the eyeshowing the anterior and posterior chambers of the eye. A schematicrepresentation of an implant 105 is positioned inside the eye such thata proximal end 110 is located in the anterior chamber 115 and a distalend 120 is located in or near the suprachoroidal space (sometimesreferred to as the perichoroidal space). The suprachoroidal space caninclude the region between the sclera and the choroid. Thesuprachoroidal space can also include the region between the sclera andthe ciliary body. In this regard, the region of the suprachoroidal spacebetween the sclera and the ciliary body may sometimes be referred to asthe supraciliary space. The suprachoroidal “space” is a potential spacebetween tissue layers that does not normally exist physiologically orhistologically. Rather, the suprachoroidal space can be artificiallycreated such as by surgical methods and devices such that an implant orother material can be implanted therein.

The implants 105 described herein can deliver therapeutics to the eye ina tailored manner. For example, a single implant can deliver a singletherapeutic to a single region of the eye. Alternatively, a singleimplant can deliver more than one therapeutic to a region of the eye byincorporating drug delivery zones. Further, multiple implants can bedelivered to multiple regions of the eye to deliver one or moretherapeutics to those regions. It should also be appreciated that theimplants described herein are not necessarily positioned between thechoroid and the sclera. The implants can be positioned at leastpartially between the ciliary body and the sclera, or at least partiallypositioned between the sclera and the choroid. The implants describedherein can also be implanted such that they extend towards the back ofthe eye and other regions in the eye as will be described herein.

FIG. 2 is a cross-sectional view of a portion of the human eye. The eyeis generally spherical and is covered on the outside by the sclera S.The retina lines the inside posterior half of the eye. The retinaregisters the light and sends signals to the brain via the optic nerve.The bulk of the eye is filled and supported by the vitreous body, aclear, jelly-like substance. The elastic lens L is located near thefront of the eye. The lens L provides adjustment of focus and issuspended within a capsular bag from the ciliary body CB, which containsthe muscles that change the focal length of the lens. A volume in frontof the lens L is divided into two by the iris I, which controls theaperture of the lens and the amount of light striking the retina. Thepupil is a hole in the center of the iris I through which light passes.The volume between the iris I and the lens L is the posterior chamberPC. The volume between the iris I and the cornea is the anterior chamberAC. Both chambers are filled with a clear liquid known as aqueous humor.

The ciliary body CB continuously forms aqueous humor in the posteriorchamber PC by secretion from the blood vessels. The aqueous humor flowsaround the lens L and iris I into the anterior chamber AC and exits theeye through the trabecular meshwork, a sieve-like structure situated atthe corner of the iris I and the wall of the eye (the corner is known asthe iridocorneal angle). Some of the aqueous humor filters through thetrabecular meshwork near the iris root into Schlemm's canal, a smallchannel that drains into the ocular veins. A smaller portion rejoins thevenous circulation after passing through the ciliary body and eventuallythrough the sclera (the uveoscleral route).

Glaucoma is a disease wherein the aqueous humor builds up within theeye. In a healthy eye, the ciliary processes secrete aqueous humor,which then passes through the angle between the cornea and the iris.Glaucoma appears to be the result of clogging in the trabecularmeshwork. The clogging can be caused by the exfoliation of cells orother debris. When the aqueous humor does not drain properly from theclogged meshwork, it builds up and causes increased pressure in the eye,particularly on the blood vessels that lead to the optic nerve. The highpressure on the blood vessels can result in death of retinal ganglioncells and eventual blindness.

Closed angle (acute) glaucoma can occur in people who were born with anarrow angle between the iris and the cornea (the anterior chamberangle). This is more common in people who are farsighted (they seeobjects in the distance better than those which are close up). The iriscan slip forward and suddenly close off the exit of aqueous humor, and asudden increase in pressure within the eye follows.

Open angle (chronic) glaucoma is by far the most common type ofglaucoma. In open angle glaucoma, the iris does not block the drainageangle as it does in acute glaucoma. Instead, the fluid outlet channelswithin the wall of the eye gradually narrow with time. The diseaseusually affects both eyes, and over a period of years the consistentlyelevated pressure slowly damages the optic nerve.

It should be appreciated that other ocular conditions besides glaucomacan be treated with the implants described herein. For example, theimplants can deliver drugs for the treatment of macular degeneration,retinal disease, proliferative vitreoretinopathy, diabetic retinopathy,uveitis, keratitis, cytomegalovirus retinitis, cystoid macular edema,herpes simplex viral and adenoviral infections. It also should beappreciated that medical conditions besides ocular conditions can betreated with the implants described herein. For example, the implantscan deliver drugs for the treatment of inflammation, infection,cancerous growth. It should also be appreciated that any number of drugcombinations can be delivered using any of the implants describedherein.

Implants

In a first embodiment, the implant 105 can have a solid body that doesnot include a flow channel such that agents are delivered into the eyeby the drug delivery implant independent of a flow channel. The implant105 can be an elongate element having a substantially uniform diameteralong its entire length as shown in FIG. 1. It should be appreciated,however, that the implants can vary widely in shape, structure and alsomaterial as will be described in more detail below. Moreover, theimplant 105 can have various cross-sectional shapes (such as a,circular, oval or rectangular shape) and can vary in cross-sectionalshape moving along its length. The shape of the implant 105 can alsovary along its length (either before or after insertion of the implant).The cross-sectional shape can be selected to facilitate easy insertioninto the eye. The implant 105 can be formed at least in part by amaterial having shape memory, such as a shape memory metal alloy, suchas Nitinol, or a heat-set polymer. The implant 105 can transition from anarrow, elongate delivery shape to its memory shape upon delivery in theeye. For example, the elongate implant can relax into a shape that iscurved, coiled, cupped, rolled, twisted, tangled and the like.

The implant can have a thin, elongated structure, such as a fiber,filament or a monofilament wire of polymer. The filamentous implant canalso include a plurality of interconnected strands, such as in a twistor braid or other woven fashion. The filamentous implant can also takeon a tangled configuration that resembles a tangled ball of string. Theimplant can also have a shorter structure such as segments of fibers, orspherical particles such as pellets, beads or deposits of polymer, gelor other material. The implant can have a structure that includes a bodyhaving an inner core that can be filled with an agent to be delivered,such as a “pumping pill” type of implant, as will be described in moredetail below. The implant can include one or more nanotubes.

The implant 105 can include a drug-eluting polymer matrix that is loadedor impregnated with a drug. The drug can elute over time into the eyefrom the implant 105 in a time-release fashion. The implant 105 or aportion of the implant can be bioabsorbable such that it need not beremoved from the eye after administration of the drug protocol. Theimplant 105 or a portion of the implant can also be non-bioabsorbable aswell. The non-bioabsorbable implant can, but need not be removed fromthe eye once the drug is fully administered. If the implant is to beremoved from the eye upon final delivery of drug, the removal andreplacement schedule can vary. For example, the implant can be removedand replaced every 1-2 years. The implant 105 can include a feature suchas a proximal loop or other structure that can be grasped allowing theimplant 105 to be retrieved and replaced. A portion of the implant 105can also be anchored, for example with structural features such asflanges, protrusions, wings, tines, or prongs, and the like that canlodge into the surrounding eye anatomy to retain its position duringdrug delivery.

As mentioned above, the implants described herein can be positionedwithin a variety of regions within the eye including the supraciliaryspace, suprachoroidal space, and further back towards the back of theeye. The suprachoroidal space (sometimes referred to as theperichoroidal space) can include the region between the sclera and thechoroid. The suprachoroidal space can also include the region betweenthe sclera and the ciliary body. In this regard, the region of thesuprachoroidal space between the sclera and the ciliary body maysometimes be referred to as the supraciliary space. For example, theimplants described herein can be positioned within different regions ofthe eye depending on the condition to be treated. An implant being usedto deliver a drug used to treat macular degeneration, for example, canbe positioned such that at least a portion of the implant is positionednear the back of the eye. An implant being used to deliver ananti-glaucoma drug can be positioned, for example, within at least aportion of the supraciliary and/or suprachoroidal space.

The implants described herein can also deliver one or more therapeuticsto select regions and structures within the eye by the formulation ofone or more drug delivery zones along the length of the implant. In anembodiment, the implant can be coated on a surface with one or moredrugs to create the one or more drug delivery zones. The implants caninclude one, two, three, or more drug delivery zones. Each drug deliveryzone can deliver one or more drugs. The drug delivery zones can beformulated depending on where the zone is oriented within the eye uponimplantation of the device. Orientation of the drug delivery zones withrespect to the adjacent tissues can be selected based on where drugdelivery is desired. For example, drugs that affect outflow of aqueous,for example through the trabecular meshwork can be embedded or deliveredfrom a drug delivery zone positioned in the anterior chamber, near thetrabecular meshwork, iris, Schlemm's canal and the like. Drugs thataffect production of aqueous from epithelial cells of the ciliary bodycan be can be embedded or delivered from a drug delivery zone positionednear the ciliary body, the epithelial cells of the ciliary body, theboundary between the ciliary body and the sclera, the supraciliaryspace, the suprachoroidal space and the like.

The implant can be implanted such that one drug delivery zone ispositioned in a first anatomical location, for example between theciliary body and the sclera, and the other drug delivery zone ispositioned in a second anatomical location. The type of drug deliveredfrom each drug delivery zone can be tailored to where in the eye anatomythe drug delivery zone is positioned. Zones positioned between theciliary body and the sclera can contain drug(s) that affect the ciliarybody, for example, a drug that acts on the ciliary body epithelial cellsto decrease aqueous humor production. This tailored formulation of thedrug delivery zones allows for a direct route of administration tointended drug targets within the eye. Drug dosage can be reducedcompared to, for example, systemic delivery or for avoiding problemswith wash-out. The implant as well as each drug delivery zone relativeto the implant can have a length that is suitable for desired deliveryof a drug in and around various structures within the eye.

FIG. 3A shows an embodiment of a drug delivery implant 105 that has anelongate, filamentous structure and extends between the region of theeye near the ciliary body towards the back of the eye. The implant 105can include one or more drug delivery zones depending on whichanatomical location of the eye is desired to be treated. More than onedisease or condition can be treated from a single implant. For example,both retinal disease and glaucoma can be treated from one implant. Itshould also be appreciated that the number of drug delivery zones canvary and that different medications can be used to treat differentportions of the eye in the different zones of the implants.

The elongate, filamentous structure can be delivered such that it trailsthrough multiple locations in the eye as shown in FIG. 3A. For example,the distal end of a single filamentous implant can be dragged into placeto a location near the back of the eye while the proximal end remainspositioned near the ciliary body. The implant having an elongate,filamentous structure can be delivered such that it takes on a differentstructure. For example, a filamentous implant can be delivered such thatit bunches or tangles up within a focused region in the eye. Theelongate, filamentous implant can also be manufactured of a materialhaving shape memory that changes from a delivery conformation to animplantation conformation, as will be discussed in more detail below.

In addition to using an elongate implant having multiple drug deliveryzones to tailor drug treatments, more than one implant 105 can bepositioned in multiple locations within the eye (see FIG. 3B). Multipleimplants 105 can be used to treat more than one condition or themultiple implants can treat a single condition by delivering one or moretherapeutic agents. Multiple pellets of drug delivery polymer or gelimpregnated with a therapeutic can be delivered in single or multiplelocations in the eye. The implants delivered to multiple locations caninclude segments of fibers, or spherical particles such as pellets,beads or deposits of polymer, gel or other material.

The dimensions of the implants can vary. In an embodiment, the implanthas a length in the range of about 0.1″ to about 0.75″. In anotherembodiment, the implant as a length of about 0.250″ to about 0.300″. Inanother embodiment, the implant as a diameter in the range of about0.002″ to about 0.015″. In another embodiment, the implant has adiameter in the range of about 0.002″ to about 0.025″. In an embodiment,the diameter if the implant is 0.012″, 0.010″, or 0.008″. In the eventthat multiple implants are used, each implant can be about 0.1″.Stacking the implants can result in a fully implanted device having alength, for example of 0.2″ to 1.0″, although the length can be outsidethis range. An embodiment of the implant is 0.250″ long, and 0.015″ inouter diameter. One embodiment of the implant is 0.300″ long. In anotherembodiment, the implant is approximately 1 mm in diameter and betweenabout 15-20 mm in length. In another embodiment, the implant isapproximately 1 mm in diameter and approximately 3 mm in length. Inanother embodiment, the implant is approximately 1 mm².

Depending on the treatment dose desired, and the delivery profile of thetherapeutic agent delivered, it may be advantageous for the implant 105to extend from the initial dissection plane near the angle of the eye,within the supraciliary and/or suprachoroidal space into the posteriorsegment of the eye or any location therebetween. The geometry of theimplant 105 can assist in the ability to prolong or control variousdosing regimes. For example, a longer implant 105, multiple implants 105or an implant 105 having a larger diameter can each result in a longerdosing potential. The implant 105 can completely fill the suprachoroidalspace to minimize any “washout” effect as well as assist in the dosing.In addition, it may be advantageous to employ a sealant, to seal anycommunication between the anterior chamber and the newly dissectedsuprachoroidal space once the implant 105 is placed. Products such asTISSEAL (Baxter Healthcare, Irvine, Calif.), fibrin glues, or smallamounts of cyanoacrylate may be used for this purpose.

As mentioned above, the elongate, filamentous implant can also bemanufactured of a material having shape memory, such as a heat-setpolymer, Nitinol or other shape-memory alloy, that changes from adelivery conformation to an implantation conformation. The implant 105can change from a delivery conformation such as that shown in FIG. 4A toan implantation conformation such as those shown in FIGS. 4B-4D. Theimplant 105 upon being released in the eye can take on its relaxed shapesuch as a coil. The coil can also take on a cup shape (see FIGS. 4C and4D) such that it hugs the curve of the eye and minimizes distortion ofsurrounding eye tissues, for example the retina if implanted near theback of the eye or the zonules if implanted near the ciliary body.

FIG. 5A shows another embodiment of an implant 105 and FIG. 5B is across-sectional view of the implant of FIG. 5A taken along lines B-B. Inthis embodiment, the implant 105 can be an elongate element having oneor more interior volumes 135 into which a drug-release material 140 canbe molded, cast, embedded or injected therein, as will be described inmore detail below. In an embodiment, the drug-release material 140 plugsthe interior volume(s) 135 and prevents fluid flow through the implantfor a period of time. An amount of drug within the drug-release material140 can elute over time from the interior volume 135, for examplethrough an opening in fluid communication with the interior volume 135,to treat a region of the eye. After a period of time, the drug-releasematerial 140 degrades and is removed from the interior volume(s) 135 ofthe implant, as will be discussed in more detail below. Alternately, thedrug release material can be nondegradable. The drug and/or adrug-release material can degrade out of a non-absorbable structure,leaving the interior volume only including a matrix of thenon-absorbable structure.

As described with previous embodiments, the implant 105 can have asubstantially uniform diameter along its entire length, although theshape of the implant 105 can vary along its length as described above.The cross-sectional shape can be selected to facilitate easy insertioninto the eye. The implant 105 can include any number of additionalstructural features 125 that aid in anchoring or retaining the implantedimplant 105 in the eye (see FIGS. 9A-9D) such as protrusions, wings,tines, or prongs that lodge into anatomy to retain the implant in place.In an embodiment, the interior volume 135 can also be used as a pathwayfor flowing material (for example, aqueous, liquid, balanced saltsolution, viscoelastic fluid, therapeutic agents, drug-release material,or the like) into the eye. U.S. Patent Publication Nos. 2007-0191863 and2009-0182421 describe exemplary implants. These applications areincorporated by reference in their entirety.

In the embodiment of FIGS. 5A-5B, the implant 105 can include aninterior volume 135 extending between at least one opening 110 at aproximal end and at least one opening 120 at a distal end. The interiorvolume 135 can be filed with a drug-release material 140 forming a plugthat can prevent substantial flow a fluid through the implant 105. Theimplant 105 having drug-release material 140 in the internal volume 135can serve as a drug delivery implant to deliver therapeutics in atime-release fashion to the anterior chamber, the suprachoroidal spaceor other regions near the eye. In an embodiment, the drug is completelyeluted from the drug-release material 140 over a selected period oftime. Further, the drug-release material 140 can degrade over anotherselected period of time such that it no longer plugs the interior volume135. As such, some flow can begin to take place through the interiorvolume 135 in the implant 105.

The walls of the implant 105 can have a solid structure or can includeone or more openings extending from an internal surface to the externalsurface through which the drug-release material 140 can elute. Theimplant 105 can also have a braided or mesh structure such that theopenings in the braided or mesh structure are spanned, or partiallyspanned, by drug-release material 140. The implant 105 can include oneor more internal reservoir(s) of drug that fluidly communicate with thesurface of the implant such that drug-release material 140 can elutefrom the reservoirs and come into contact with adjacent tissues. Thereservoirs can be refillable and/or a single-use reservoir. Thereservoirs can be opened such as by a laser or other energy source toapply a small electrical voltage to release the desired dose of thedrug(s) on demand.

The implants 105 described herein can deliver more than one type of drugsimultaneously. In an embodiment, the implant 105 can include a seconddrug, which may be incorporated into the drug-release material, theimplant itself or both. The implant 105 can release one, two, three,four or even more drugs. The drug-release material 140 can include morethan a single therapeutic. Alternatively, the drug-release material 140can be divided into drug delivery zones, such as one, two, three, ormore drug delivery zones within or on the implant 105. For example, adistal end of the implant can include a first zone of drug-releasematerial 140 and a proximal end of the implant can include a second zoneof drug-release material 140 that elutes a different drug. Further, eachdrug delivery zone can deliver one or more drugs. Implants having drugdelivery zones are described in more detail in application Ser. No.12/939,033, filed Nov. 3, 2010, which is incorporated herein byreference in its entirety. The implants 105 described herein can alsohave one or more coatings or be covered by one or more films. Theimplant 105 can be coated with one or more surface layers of materials,such as a slow-release substance to have prolonged effects on localtissue surrounding the implant 105. As such a material can be releasedfrom the surface of the implant and a different material can be releasedfrom the interior of the implant.

As mentioned above, the implants described herein can, but need not beremoved from the eye upon completion of a drug delivery protocol. If theimplant is to be removed from the eye upon final delivery of drug, theremoval and replacement schedule can vary. For example, the implant canbe removed and replaced every 1-2 years. Alternatively, the implants canbe left within the eye after full elution of drug from the drug-releasematerial and degradation of the drug-release material from the interiorvolume. In an embodiment, the implant can be biodegradable and need notbe removed from the eye after administration of the drug protocol. Thebiodegradable material selected for the implant body can have a similaror longer degradation rate than the drug-release material 140 within thecore of the implant 105 or spanning the openings of the implant 105, butwill generally have a longer degradation rate than the elution rate ofthe drug from the drug-release material, as will be discussed in moredetail below.

Drug-Release Material

As used herein, “drug-release,” “drug-eluting,” “drug-loaded” materialsand the like refer to materials that are or can have a substance such asa drug or therapeutic agent dissolved, entrapped, encapsulated, loaded,impregnated, adsorbed, or otherwise embedded within the material forcontrolled delivery of the substance into tissues. It should beappreciated that use of the term “drug” is not limiting regarding whatsubstance is admixed with the drug-release material. The drug-releasematerial can include essentially any biocompatible polymer, co-polymer,terpolymer, polymer blend, as well as non-polymeric substances andmatrices. The drug-release material can include biodegradable materialsincluding bioerodible, bioabsorbable, and bioresorbable polymericmaterials. Examples of non-polymeric materials that can be employedinclude, but are not limited to, metal oxide structures, metallicmatrices and other porous substances. The drug-release material can bedesigned as blends, films, matrices, microspheres, nanoparticles,pellets, coatings, films, cores etc.

The drug-release material can be biodegradable polymers including, butnot limited to poly(lactic-co-glycolic) acid (“PLGA”), polylactide,polyglycolide, polycaprolactone, or other polyesters, poly(orthoesters),poly(aminoesters), polyanhydrides, polyorganophosphazenes, or anycombination thereof. Other biodegradable polymers known to those skilledin the art may also be applied and selected based on the desiredmechanical properties and polymer-drug interaction.

In another embodiment, the polymer of the drug-release material isnon-degradable. For example, the polymer of the drug-release materialmay be ethyl cellulose, poly(butyl acrylate), poly(urethanes), siliconeresins, nylon, ammonium polyacrylate, acrylamide copolymers,acrylate/acrylamide copolymers, acrylate/ammonium acrylate copolymers,acrylate/alkyl acrylate copolymers, acrylate/carbamate copolymers,acrylate/dimethylaminoethyl methacrylate copolymers, ammonium acrylatecopolymers, styrene/acrylate copolymers, vinyl acetate/acrylatecopolymers, aminomethylpropanol/acrylate/dimethylaminoethylmethacrylatecopolymers, or any combination thereof. Other non-degradable polymersknown to those skilled in the art may also be applied and selected basedon the desired mechanical properties and polymer-drug interaction.

In some embodiments, the drug-release material can include a hydrogel,including, but not limited to, polyhydroxyethylmethacrylate (pHEMA), asilicone, agarose, alginate, chitosan, and hyaluronic acid. Thedrug-release material can also include a viscoelastic composition suchas a viscoelastic preparation of sodium hyaluronate such as AMVISC (fromAnika Therapeutics, Inc.), OCUCOAT (Bausch & Lomb), PROVIS, VISCOAT,DUOVISC, CELLUGEL (from Alcon Labs), BIOVISC, VITRAX (from Allergan),BIOLON (from Bio-Technology General), STAARVISC (from AnikaTherapeutics/Staar Surgical), SHELLGEL (from Anika Therapeutics/CytosolOpthalmics), HEALON (Abbott Medical Optics), UNIVISC (from Novartis),and the like. Other hydrogels known to those skilled in the art may alsobe applied and selected based on the desired mechanical properties andhydrogel-drug interaction. The drug-release material may, in some cases,form a gel within a pH range. In another embodiment, the drug-releasematerial may transition between a liquid and a gel at a criticaltemperature. In another embodiment, a physical or chemical interactionbetween the hydrogel or viscoelastic can be employed to regulate thedrug release rate.

Release of the drug from the drug-release material can be controlled, inpart, by the composition of the polymer in the drug-release material.Various factors such as the mechanical strength, swelling behavior,capacity to undergo hydrolysis all can affect release rates of thedrug-release material, as is known in the art. The polymer can beengineered and specifically designed and/or selected to provide thedrug-release material with the desired biodegradation rate and releaseprofile of the drug from for a selected duration. The release profilecan be manipulated such as by adjusting features of the composition likepolymer(s), changing the ratio of components of the polymeric material,ratio of the monomers in the co-polymer drug(s), level of drug loading,surface area and dimensions of the implant etc. The ratio of polymer todrug can vary as well. For example, the polymer to drug ratio caninclude 1:2, 1:4, 1:8, 1:16, 1:32, 1:64, 1:128, 1:256, 1:512, or anyother desirable ratio.

The drug-release material can release drug over a period of time. In anembodiment, the drug-release material releases at least one drug for atleast 12 hours, at least 18 hours, at least 24 hours, at least 48 hours,at least 3 days, at least 7 days, at least 14 days, at least 30 days, atleast 60 days, at least 90 days, at least 100 days, at least 120 days,at least 150 days, at least 180 days, at least 200 days, at least 250days, at least 300 days, at least 350 days, at least 400 days, or evenlonger.

The drug-release material can exhibit multi-phasic drug releaseprofiles, which can include an initial burst of drug and a period ofsustained drug release as is known in the art. The release profile canbe manipulated such as by adjusting features of the composition likepolymer(s), drug(s), level of drug loading, surface area and dimensionsof the implant etc. The rate can be episodic or periodic, or such thatit is suitable for ocular and intra-ocular drug delivery having suitablerelease kinetics. The initial burst can be shortened by removing orrinsing the blend of drug at or near the surface of the implant or drugcore or by coating the composition with a polymer that can be drug freeor have a reduced drug content. In an embodiment, the implant can beloaded with a drug and premature or uncontrolled leakage of the drug isessentially avoided. Further, the drug can be embedded in a structurethat regulates the release according to zero-order kinetic model. Suchstructures can be created using nano-technology and can include metaloxide or polymer matrices or other highly-controlled porous structures.The implant can also include small reservoir(s) of drug that can beopened such as by a laser or other energy source to apply a smallelectrical voltage to release the desired dose of the drug(s) on demand.

The drug-release material itself can dissolve, degrade, erode, absorb,or resorb over a period of time as well. In an embodiment, thedrug-release material degrades from the interior volume of the implantover a period of at least 12 hours, at least 18 hours, at least 24hours, at least 48 hours, at least 3 days, at least 7 days, at least 14days, at least 30 days, at least 60 days, at least 90 days, at least 100days, at least 120 days, at least 150 days, at least 180 days, at least200 days, at least 250 days, at least 300 days, at least 350 days, atleast 400 days, or even longer.

In an embodiment, the drug-release material can prevent substantial flowof fluid through the implant over a period of at least 12 hours, atleast 18 hours, at least 24 hours, at least 48 hours, at least 3 days,at least 7 days, at least 14 days, at least 30 days, at least 60 days,at least 90 days, at least 100 days, at least 120 days, at least 150days, at least 180 days, at least 200 days, at least 250 days, at least300 days, at least 350 days, at least 400 days, or even longer.

In an embodiment, the implant 105 includes an interior volume thatresembles a flow lumen having at least one inflow port at a first endand at least one outflow port at a second end. After a period of atleast 12 hours, at least 18 hours, at least 24 hours, at least 48 hours,at least 3 days, at least 7 days, at least 14 days, at least 30 days, atleast 60 days, at least 90 days, at least 100 days, at least 120 days,at least 150 days, at least 180 days, at least 200 days, at least 250days, at least 300 days, at least 350 days, at least 400 days, or evenlonger, the drug-release material does not prevent substantial flow offluid through the implant.

In an embodiment, the internal volume 135 of the implant 105 is filledwith poly(lactic-co-glycolic acid) (PLGA) microspheres having abiodegradation rate such that after at least a period of dayssubstantially all the drug has been eluted from the drug-releasematerial and the drug-release material has degraded by at least apercent from the interior volume 135 of the implant 105. In anembodiment, substantially all the drug has eluted from the drug-releasematerial in 180 days. In an embodiment, the drug-release material hasdegraded by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85% or more percent from the interior volume135 of the implant 105.

Manufacturing Techniques

The implants described herein can be manufactured as is known in theart. The implants can be machined or laser ablated from a unitary rod orblock of stock material with the material subtracted or removed, leavingfeatures behind. Alternatively, separate parts of the implant can bemanufactured separately and assembled onto the implant. The implant canbe manufactured by one or more injection molding or dip coatingprocesses. The implants can be made of various materials, including, forexample, polyimide, Nitinol, platinum, stainless steel, molybdenum,PVDF, silicone, or any other suitable polymer, metal, metal alloy, orceramic biocompatible material or combinations thereof. Other materialsof manufacture or materials with which the implant can be coated ormanufactured entirely include Silicone, PTFE, ePTFE, differentialfluoropolymer, FEP, FEP laminated into nodes of ePTFE, silver coatings(such as via a CVD process), gold, prolene/polyolefins, polypropylene,poly(methyl methacrylate) (PMMA), acrylic, PolyEthylene Terephthalate(PET), Polyethylene (PE), PLLA, and parylene. The implants can bereinforced with polymer, Nitinol, or stainless steel braid or coiling orcan be a co-extruded or laminated tube with one or more materials thatprovide acceptable flexibility and hoop strength for adequate lumensupport and drainage through the lumen. The implant can alternately bemanufactured of nylon (polyamide), PEEK, polysulfone, polyamideimides(PAI), polyether block amides (Pebax), polyurethanes, thermoplasticelastomers (Kraton, etc), and liquid crystal polymers. The implants canbe at least partially manufactured of a mesh or braided structure formedof two or more interwoven strands, fibers, or threads of material. Theinterwoven strands can be arranged in a pattern that formsdiamond-shaped holes or openings therebetween or openings of othershapes. The braided structure can be positioned over or otherwisecombined with a solid tube. The implant can surround a core of drug thatcan be released through openings in the structure of the implant.

Embodiments in which the implant includes a drug-release materialembedded within the interior volume can be prepared as is known in theart, for example, by simultaneously dissolving the polymer, drug, and,if present, optional component(s) in an organic solvent system capableof forming a homogenous solution of the polymer, drug, and optionalcomponent(s), solvent-casting the solution and then evaporating thesolvent to leave behind a uniform, homogenous blend of polymer, drug andoptional component(s).

The drug-polymer matrices can be fabricated by known methods (e.g.,fiber spinning, electro-spinning, solvent casting, injection molding,thermoforming, etc.) to produce a desired structure for the implant.Depending on the thermal stability of the drug and the polymer, thearticles can be shaped by conventional polymer-forming techniques suchas extrusion, sheet extrusion, blown film extrusion, compressionmolding, injection molding, thermoforming, spray drying, injectableparticle or microsphere suspension, and the like to form drug deliveryimplants The drug-release material can be prepared by methods known inthe art for forming biocompatible composites. In another embodiment, thedrug can be incorporated into the structural material of the implantitself.

Embodiments in which the implant is coated with the drug-releasematerial, the coatings can be spray-coated, dip coated, printed, orotherwise deposited can be prepared as is known in the art. The coatingcan be uniform or non-uniform such as dots or stripes or other patternof material. The implant can include one or more layers of the coating.For example, a first or base layer can provide adhesion, a main layercan hold the drug to be eluted and a top coat can be used to slow downthe release of the drug and extend its effect.

In some cases, it may be advantageous to have multiple main and top coatlayers to provide varying drug release profiles. The implant can alsoinclude drug-release material on at least a surface of the implant thatis in the form of a polymeric film.

Delivery Device

A variety of implantation systems can be used to deliver the drugdelivery implant(s) described herein, such as the delivery devicesdescribed in U.S. Patent Publication number 2010-0137981, which isincorporated by reference herein in its entirety. FIGS. 6A-6D illustrateexamples of an implantation system 805 that can be used to deliver someembodiments of the implants described herein. The implantation system805 can generally include a proximal handle component 810 and a distalimplantation component 815. The implantation component 815 is shown asbeing curved, but it should be appreciated that it could also bestraight. The curvature of the implantation component 815 can vary. Forexample, the radius of curvature can be between about 3 mm to 50 mm andthe curve can cover from 0 degrees to 180 degrees. In an embodiment, theradius of curvature can be around 12 mm.

The proximal handle component 810 can include an actuator 820 to controlthe release of the drug delivery implant(s) 105 from the elongatechannel 825 of the implantation component 815 through which the implant105 can be inserted longitudinally and into the target location in theeye. At least a portion of the distal region of the implant 105 canextend beyond the distal region of the implantation component 815 suchthat clogging is avoided during delivery. The implantation component 815can also include a pusher 830 or other type of component that aids torelease the implant 105 from the delivery device and into the eye. Thepusher 830 can be coupled to the actuator 820 and act to push out theimplant 105 from the distal end of the implantation component 815 uponsliding the actuator button 820 in a distal direction along arrow A (seeFIGS. 6A-6B).

Alternatively, the actuator button 820 can be coupled to theimplantation component 815 such that sliding the actuator button 820proximally along arrow A retracts the implantation component 815 andreleases the implant 105 (see FIGS. 6C-6D). In this embodiment, thepusher 830 remains fixed within the delivery device 805 such as at tube817 (as opposed to being slidably coupled with tube 817 as shown inFIGS. 6A-6B) and prevents the implant 105 from traveling proximally withthe implantation component 815 as it is retracted. It should beappreciated that although FIGS. 6A-6D illustrate the delivery of asingle implant 105, more than one implant 105 can be delivered in theeye with one application of the delivery device 805. The one or moreimplants 105 can be delivered to a single location in the eye or spreadout over multiple locations as described above.

During implantation, the distal region of the implantation component 815can penetrate through a small, corneal incision to access the anteriorchamber AC. In this regard, the single incision can be made in the eye,such as within the limbus of the cornea. In an embodiment, the incisionis very close to the limbus, such as either at the level of the limbusor within 2 mm of the limbus in the clear cornea. The implantationcomponent 815 can be used to make the incision or a separate cuttingdevice can be used. For example, a knife-tipped device or diamond knifecan be used to initially enter the cornea. A second device with aspatula tip can then be advanced over the knife tip wherein the plane ofthe spatula is positioned to coincide with the dissection plane.

The corneal incision can have a size that is sufficient to permitpassage of the drug delivery implant(s) 105 in the implantationcomponent 815 therethrough. In an embodiment, the incision is about 1 mmin size. In another embodiment, the incision is no greater than about2.85 mm in size. In another embodiment, the incision is no greater thanabout 2.85 mm and is greater than about 1.5 mm. It has been observedthat an incision of up to 2.85 mm is a self-sealing incision.

In one embodiment, after insertion through the incision the implantationcomponent 815 can be advanced into the anterior chamber AC along apathway that enables the implant 105 to be delivered from the anteriorchamber toward the angle of the eye and into the supraciliary and/or thesuprachoroidal space (see FIG. 7). With the implantation component 815positioned for approach, the implantation component 815 can be advancedfurther into the eye towards the angle of the eye where the implantationcomponent 815 can bluntly dissect and/or sharply penetrate tissues nearthe angle of the eye such that the supraciliary and/or suprachoroidalspace can be entered. It should be appreciated that although FIG. 7shows a single implant 105 being delivered into a location in the eye,more than one implant can be delivered using a single implantationcomponent 815 and delivered during a single application using thedelivery device 805.

The scleral spur is an anatomic landmark on the wall of the angle of theeye. The scleral spur is above the level of the iris but below the levelof the trabecular meshwork. In some eyes, the scleral spur can be maskedby the lower band of the pigmented trabecular meshwork and be directlybehind it. The implantation component 815 can travel along a pathwaythat is toward the scleral spur such that the implantation component 815passes near the scleral spur on the way to the suprachoroidal space. Inan embodiment the implantation component 815 penetrates the scleral spurduring delivery. In another embodiment, the implantation component 815does not penetrate the scleral spur during delivery. The implantationcomponent 815 can abut the scleral spur and move downward to dissect thetissue boundary between the sclera and the ciliary body, the dissectionentry point starting just below the scleral spur near the iris root orthe iris root portion of the ciliary body.

It should be appreciated that the pathway the implantation component 815travels into the supraciliary and/or suprachoroidal space can vary. Theimplantation component 815 can bluntly dissect and/or sharply penetratetissues near the angle of the eye such that the supraciliary and/orsuprachoroidal space can be entered. In one example, the implantationcomponent 815 penetrates the iris root. In another example, theimplantation component 815 enters through a region of the ciliary bodyor the iris root part of the ciliary body near its tissue border withthe scleral spur. In another example, the implantation component 815 canenter above or below the scleral spur. The another example, theimplantation component 815 can enter through the trabecular meshwork.

The implantation component 815 can approach the angle from the same sideof the anterior chamber as the deployment location such that theimplantation component 815 does not have to be advanced across the iris.Alternately, the implantation component 815 can approach the angle fromacross the anterior chamber such that the implantation component 815 isadvanced across the iris and/or the anterior chamber toward the oppositeangle (see FIG. 7). The implantation component 815 can approach theangle along a variety of pathways. The implantation component 815 doesnot necessarily cross over the eye and does not intersect the centeraxis of the eye. In other words, the corneal incision and the locationwhere the implantation component 815 enters the angle can be in the samequadrant. Also, the pathway of the device from the corneal incision tothe angle ought not to pass through the centerline of the eye to avoidinterfering with the pupil. The surgeon can rotate or reposition thehandle of the delivery device 805 in order to obtain a proper approachtrajectory for the implantation component 815.

The implantation component 815 with the implant 105 positioned thereincan be advanced through to the supraciliary and/or suprachoroidal space.In one example, the implantation component 815 can be advanced such thatit penetrates an area of fibrous attachment between the scleral spur andthe ciliary body. This area of fibrous attachment can be approximately 1mm in length. Once the distal tip of the implantation component 815penetrates and is urged past this fibrous attachment region, it thenmore easily causes the sclera to peel away or otherwise separate fromthe choroid as it follows the inner curve of the sclera and forms thesuprachoroidal space. The implantation component 815 can be continuouslyadvanced into the eye. The dissection plane of the implantationcomponent 815 follows the curve of the inner scleral wall such that itbluntly dissects the boundary between tissue layers of the scleral spurand the ciliary body. A combination of the tip shape, material, materialproperties, diameter, flexibility, compliance, coatings, pre-curvatureetc. of the implantation component 815 make it more inclined to followan implantation pathway that mirrors the curvature of the inner wall ofthe sclera and between tissue layers such as the sclera and choroid. Thedynamics of the implantation component is described in more detail inU.S. Patent Publication number 2010-0137981, which is incorporated byreference herein in its entirety.

As described above, the implant 105 can be positioned within a varietyof regions of the eye using the delivery device 805. For example, theimplant 105 can be positioned within the supraciliary space, thesuprachoroidal space or other locations deeper in the eye such as towardthe back of the eye. Other locations for implant 105 are also possible.It should also be appreciated that multiple depositions of a pluralityof drug delivery implants 105 can be performed in various zones of theeye during a single approach and dissection using the delivery device805.

In some embodiments, once the implant 105 is released within the eye thedrug-release material can slowly elute drug such that the implant 105delivers therapy to the eye in a time-release manner. After a period oftime, the drug is largely eluted from the drug-release material. Thedrug-release material can also degrade over time leaving an openinterior volume of the implant 105. The implant 105 can be left in placesuch that the open interior volume can provide a flow channel foraqueous to exit the anterior chamber. Alternative, the implant 105 canbe recharged with drug-release material or the implant 105 can beremoved from the eye either by manual removal or by biodegradation ofthe implant 105 within the eye.

The implants can be delivered pre-loaded with the drug-release materialwithin the interior volume or the implants can be filled with thedrug-release material upon delivery into the eye. FIGS. 8, and FIGS.9A-9D illustrate examples of an implantation system 305 that can be usedto deliver an implant 605 that can be filled with a drug-releasematerial 610 upon delivery into the eye. It should be appreciated thatthese implantation systems 305 are for illustration and that variationsin the structure, shape and actuation of the implantation system 305 arepossible. The implantation system 305 can generally include a proximalhandle component 310 and a distal implantation component 320. Theimplantation component 320 is shown as being curved, but it should beappreciated it could also be straight. The curvature of the implantationcomponent 320 can vary. For example, the radius of curvature can bebetween about 3 mm to 50 mm and the curve can cover from 0 degrees to180 degrees. In an embodiment, the radius of curvature can be around 12mm. The proximal handle component 310 can include an actuator 420 tocontrol the release of an implant from the implantation component 320into the target location in the eye.

The delivery component 320 can include an elongate applier 515 that caninsert longitudinally through the implant 605 and a sheath 510 that canbe positioned axially over the applier 515. The sheath 510 can aid inthe release of the implant 605 from the delivery component 320 into thetarget location in the eye. The actuator 420 can be used to control theapplier 515 and/or the sheath 510. For example, the sheath 510 can beurged in a distal direction relative to the applier 515 to push theimplant 605 off the distal end of the applier 515. Alternately, thesheath 510 can be fixed relative to the handle component 310. In thisembodiment, the sheath 510 can act as a stopper that impedes the implant105 from moving in a proximal direction as the applier 515 is withdrawnproximally from the implant 605 upon actuation of the actuator 420. Theapplier 515 can be extended distally relative to the sheath 310.Movement of the actuator 420, such as in the proximal direction, cancause the applier 515 to slide proximally into the sheath 510. Thiseffectively pushes the implant 605 off the distal end of the applier 515and releases the implant 605 in a controlled fashion such that thetarget positioning of the implant 605 within the suprachoroidal space ismaintained.

As the implant 605 is released, the applier 515 is withdrawn from theinternal volume of the implant 605. A drug-release material 610 can beinjected into the internal volume 635 of the implant 605 as the applier515 is withdrawn. FIGS. 9A-9D show the interior volume of an implant 605being injected with a drug-release material 610 as the applier 515 iswithdrawn from the implant 605. In this embodiment, the applier 515 caninclude a bore 620 through which the drug-release material 610 can beinjected into the internal volume 635 of the implant 605

In an alternative embodiment shown in FIGS. 10-11, a distal deposition710 of material can be deposited at or near the distal end of theimplant 705 prior to and/or during withdrawal of the applier 515 fromthe bore. The distal deposition 710 can be used to hydro-dissect a spacebetween tissue layers, for example by viscodissection, to further expandan area or create a “lake” 725 between the tissue layers at or near thedistal end of the implant 705, such that the layers are no longerstrongly adhesed and/or the tissues apposed. The lake 725 can beentirely enclosed by tissue and allow for the accumulation of fluidbetween the tissues. In an embodiment, the distal deposition 710 can beflowed into the suprachoroidal space, such as through a deliveryinstrument as shown in FIG. 10. The distal deposition 710 is flowed intothe eye with a pressure sufficient to form a dissection plane within thesuprachoroidal space such that the fluid then accumulates within thesuprachoroidal space so as to form a lake 725. The distal deposition 710can be formed within the suprachoroidal space such that the implant 705is positioned with its proximal end in communication with the anteriorchamber AC and its distal end positioned such that the distal deposition710 can be flowed into the suprachoroidal space. It should beappreciated that the distal deposition 710 of material may or may notalso fill the interior volume of the implant 705.

The distal deposition 710 can be a viscoelastic material, such ashyaluronic acid, that is loaded with a drug or other active agent fromwhich the drug or other active agent can elute over time. It should alsobe appreciated that the distal deposition 710 need not be loaded with adrug or an active agent. The viscoelastic material can allow for thediffusion of fluid therethrough. In this embodiment, aqueous fluid fromthe anterior chamber AC can flow through the implant 705 as well asthrough and around the distal deposition 710 forming the lake 725.

The distal deposition 710 can be protected from the aqueous fluid of theanterior chamber AC such that the rate of degradation of thedrug-release material can be extended. In an embodiment, the distaldeposition 710 deposited near the distal end of the implant 705 isprotected from exposure to the aqueous and has a degradation rate thatis at least, and preferably longer than 12 hours. The deposited materialcan result in the formation of a void between the tissue layers thatremains after degradation of the material. The lake creates a volumewhere the tissues can be permanently detached or weakly adhesed andscarring together is avoided.

Therapeutics

The devices described herein can be used to delivery essentially anyactive substance. As used herein, “substance,” “drug” or “therapeutic”is an agent or agents that ameliorate the symptoms of a disease ordisorder or ameliorate the disease or disorder including, for example,small molecule drugs, proteins, nucleic acids, polysaccharides, andbiologics or combination thereof. Therapeutic agent, therapeuticcompound, therapeutic regimen, or chemotherapeutic include conventionaldrugs and drug therapies, including vaccines, which are known to thoseskilled in the art. Therapeutic agents include, but are not limited to,moieties that inhibit cell growth or promote cell death, that can beactivated to inhibit cell growth or promote cell death, or that activateanother agent to inhibit cell growth or promote cell death. Optionally,the therapeutic agent can exhibit or manifest additional properties,such as, properties that permit its use as an imaging agent, asdescribed elsewhere herein. Exemplary therapeutic agents include, forexample, cytokines, growth factors, proteins, peptides orpeptidomimetics, bioactive agents, photosensitizing agents,radionuclides, toxins, anti-metabolites, signaling modulators,anti-cancer antibiotics, anti-cancer antibodies, angiogenesisinhibitors, radiation therapy, chemotherapeutic compounds or acombination thereof. The drug may be any agent capable of providing atherapeutic benefit. In an embodiment, the drug is a known drug, or drugcombination, effective for treating diseases and disorders of the eye.In non-limiting, exemplary embodiments, the drug is an antiinfectiveagent (e.g., an antibiotic or antifungal agent), an anesthetic agent, ananti-VEGF agent, an anti-inflammatory agent, a biological agent (such asRNA), an intraocular pressure reducing agent (i.e., a glaucoma drug), ora combination thereof. Non-limiting examples of drugs are providedbelow.

A variety of therapeutic agents can be delivered using the drug deliveryimplants described herein, including: anesthetics, analgesics, celltransport/mobility impending agents such as colchicine, vincristine,cytochalasin B and related compounds; antiglaucoma drugs includingbeta-blockers such as timolol, betaxolol, atenolol, and prostaglandins,lipid-receptor agonists or prostaglandin analogues such as bimatoprost,travoprost, latanoprost, unoprostone etc; alpha-adrenergic agonists,brimonidine or dipivefrine, carbonic anhydrase inhibitors such asacetazolamide, methazolamide, dichlorphenamide, diamox; andneuroprotectants such as nimodipine and related compounds.

Additional examples include antibiotics such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, gentamycin, and erythromycin;antibacterials such as sulfonamides, sulfacetamide, sulfamethizole andsulfisoxazole; anti-fungal agents such as fluconazole, nitrofurazone,amphotericin B, ketoconazole, and related compounds; anti-viral agentssuch as trifluorothymidine, acyclovir, ganciclovir, DDI, AZT, foscamet,vidarabine, trifluorouridine, idoxuridine, ribavirin, proteaseinhibitors and anti-cytomegalovirus agents; antiallergenics such asmethapyriline; chlorpheniramine, pyrilamine and prophenpyridamine;anti-inflammatories such as hydrocortisone, dexamethasone, fluocinolone,prednisone, prednisolone, methylprednisolone, fluorometholone,betamethasone and triamcinolone; decongestants such as phenylephrine,naphazoline, and tetrahydrazoline; miotics, muscarinics andanti-cholinesterases such as pilocarpine, carbachol, di-isopropylfluorophosphate, phospholine iodine, and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine; sympathomimetics such as epinephrine andvasoconstrictors and vasodilators; Ranibizumab, Bevacizamab, andTriamcinolone.

Antiinflammatories, such as non-steroidal anti-inflammatories (NSAIDs)may also be delivered, such as cyclooxygenase-1 (COX-1) inhibitors(e.g., acetylsalicylic acid, for example ASPIRIN from Bayer AG,Leverkusen, Germany; ibuprofen, for example ADVIL from Wyeth,Collegeville, Pa.; indomethacin; mefenamic acid), COX-2 inhibitors(CELEBREX from Pharmacia Corp., Peapack, N.J.; COX-1 inhibitors),including a prodrug NEPAFENAC; immunosuppressive agents, for exampleSirolimus (RAPAMUNE, from Wyeth, Collegeville, Pa.), or matrixmetalloproteinase (MMP) inhibitors (e.g., tetracycline and tetracyclinederivatives) that act early within the pathways of an inflammatoryresponse. Anticlotting agents such as heparin, antifibrinogen,fibrinolysin, anti clotting activase, etc., can also be delivered.

Antidiabetic agents that may be delivered using the disclosed implantsinclude acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide,tolbutamide, insulin, aldose reductase inhibitors, etc. Some examples ofanti-cancer agents include 5-fluorouracil, adriamycin, asparaginase,azacitidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine,chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine,dacarbazine, dactinomycin, daunorubicin, doxorubicin, estramustine,etoposide, etretinate, filgrastin, floxuridine, fludarabine,fluorouracil, fluoxymesterone, flutamide, goserelin, hydroxyurea,ifosfamide, leuprolide, levamisole, lomustine, nitrogen mustard,melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,pentostatin, pipobroman, plicamycin, procarbazine, sargramostin,streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard,vinblastine, vincristine and vindesine.

Hormones, peptides, steroids, nucleic acids, saccharides, lipids,glycolipids, glycoproteins, and other macromolecules can be deliveredusing the present implants. Examples include: endocrine hormones such aspituitary, insulin, insulin-related growth factor, thyroid, growthhormones; heat shock proteins; immunological response modifiers such asmuramyl dipeptide, cyclosporins, interferons (including α, β and γinterferons), interleukin-2, cytokines, FK506 (anepoxy-pyrido-oxaazcyclotricosine-tetrone, also known as Tacrolimus),tumor necrosis factor, pentostatin, thymopentin, transforming factorbeta2, erythropoetin; antineogenesis proteins (e.g., anti-VEGF,Interferons), among others and anticlotting agents includinganticlotting activase. Further examples of macromolecules that can bedelivered include monoclonal antibodies, brain nerve growth factor(BNGF), ciliary nerve growth factor (CNGF), vascular endothelial growthfactor (VEGF), and monoclonal antibodies directed against such growthfactors. Additional examples of immunomodulators include tumor necrosisfactor inhibitors such as thalidomide.

In addition, nucleic acids can also be delivered wherein the nucleicacid may be expressed to produce a protein that may have a variety ofpharmacological, physiological or immunological activities. Thus, theabove list of drugs is not meant to be exhaustive. A wide variety ofdrugs or agents may be used in the present invention, withoutrestriction on molecular weight, etc.

Other agents include anti-coagulant, an anti-proliferative, imidazoleantiproliferative agent, a quinoxaline, a phsophonylmethoxyalkylnucleotide analog, a potassium channel blocker, and/or a syntheticoligonucleotide,5-[1-hydroxy-2-[2-(2-methoxyphenoxyl)ethylamino]ethyl]-2-methylbenzenesulfonamide,a guanylate cyclase inhibitor, such as methylene blue, butylatedhydroxyanisole, and/or N-methylhydroxylamine, 2-(4-methylaminobutoxy)diphenylmethane, apraclonidine, a cloprostenol analog or a fluprostenolanalog, a crosslinked carboxy-containing polymer, a sugar, and water, anon-corneotoxic serine-threonine kinase inhibitor, a nonsteroidalglucocorticoid antagonist, miotics (e.g., pilocarpine, carbachol, andacetylcholinesterase inhibitors), sympathomimetics (e.g., epinephrineand dipivalylepinephxine), beta-blockers (e.g., betaxolol, levobunololand timolol), carbonic anhydrase inhibitors (e.g., acetazolamide,methazolamide and ethoxzolamide), and prostaglandins (e.g., metabolitederivatives of arachidonic acid, or any combination thereof.

Additional examples of beneficial drugs that may be employed in thepresent invention and the specific conditions to be treated or preventedare disclosed in Remington, supra; The Pharmacological Basis ofTherapeutics, by Goodman and Gilman, 19th edition, published by theMacMillan Company, London; and The Merck Index, 13th Edition, 1998,published by Merck & Co., Rahway, N.J., which is incorporated herein byreference.

It should be appreciated that other ocular conditions besides glaucomacan be treated with the drug delivery implants described herein. Forexample, the compositions and methods disclosed herein can be used totreat a variety of diseases and/or conditions, for example: eyeinfections (including, but not limited to, infections of the skin,eyelids, conjunctivae, and/or lacrimal excretory system), orbitalcellulitis, dacryoadenitis, hordeolum, blepharitis, conjunctivitis,keratitis, corneal infiltrates, ulcers, endophthalmitis,panophthalmitis, viral keratitis, fungal keratitis herpes zosterophthalmicus, viral conjunctivitis, viral retinitis, uveitis,strabismus, retinal necrosis, retinal disease, vitreoretinopathy,diabetic retinopathy, cytomegalovirus retinitis, cystoids macular edema,herpes simplex viral and adenoviral injections, scleritis, mucormycosis,canaliculitis, acanthamoeba keratitis, toxoplasmosis, giardiasis,leishmanisis, malaria, helminth infection, etc. It also should beappreciated that medical conditions besides ocular conditions can betreated with the drug delivery implants described herein. For example,the implants can deliver drugs for the treatment of inflammation,infection, cancerous growth. It should also be appreciated that anynumber of drug combinations can be delivered using any of the implantsdescribed herein.

While this specification contains many specifics, these should not beconstrued as limitations on the scope of what is claimed or of what maybe claimed, but rather as descriptions of features specific toparticular embodiments. Certain features that are described in thisspecification in the context of separate embodiments can also beimplemented in combination in a single embodiment. Conversely, variousfeatures that are described in the context of a single embodiment canalso be implemented in multiple embodiments separately or in anysuitable sub-combination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination can in some casesbe excised from the combination, and the claimed combination may bedirected to a sub-combination or a variation of a sub-combination.Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. Only a few examples and implementations are disclosed.Variations, modifications and enhancements to the described examples andimplementations and other implementations may be made based on what isdisclosed.

What is claimed is:
 1. A method of implanting an ocular implant fortreating an ocular disorder of an eye, comprising: forming aself-sealing incision in the cornea of the eye into the anterior chamberof the eye; introducing an implant through the incision into theanterior chamber, the implant comprising: a proximal end with at leastone inflow port; a distal end with at least one outflow port; and aninternal lumen extending through the implant between the at least oneinflow port and at least one outflow port, wherein the implant ismounted on an implantation instrument having a delivery wire extendingthrough the internal lumen of the implant; positioning the implant inthe eye using the implantation instrument and the delivery wire on whichthe implant is mounted; withdrawing the delivery wire from the internallumen of the implant; and injecting drug-release material through thedelivery wire as the delivery wire is being withdrawn from the internallumen of the implant filling the internal lumen of the implant with thedrug-release material.
 2. The method of claim 1, further comprisingpreventing fluid flow through the internal lumen of the implant with thedrug-release material.
 3. The method of claim 2, wherein thedrug-release material is configured to degrade over a period of timefrom the internal lumen of the implant.
 4. The method of claim 3,wherein the period of time is selected from the group consisting of atleast 12 hours, at least 24 hours, at least 3 days, at least 14 days, atleast 30 days, at least 120 days, and at least one year.
 5. The methodof claim 3, further comprising creating a flow pathway through theinternal lumen of the implant between the at least one inflow port andthe at least one outflow port upon degradation of the drug-releasematerial over the period of time.
 6. The method of claim 5, furthercomprising positioning the distal end of the implant between a first andsecond tissue layer and into fluid communication with the suprachoroidalspace.
 7. The method of claim 6, further comprising releasing theimplant from the delivery wire.
 8. The method of claim 7, furthercomprising conducting aqueous through the flow pathway from the anteriorchamber into the suprachoroidal space.
 9. The method of claim 3, whereinthe drug-release material is impregnated with at least one therapeuticagent.
 10. The method of claim 9, wherein the at least one therapeuticagent is released over the period of time.
 11. The method of claim 9,wherein the drug-release material comprises nanostructures facilitatingzero order kinetic release of the at least one therapeutic agent. 12.The method of claim 1, wherein the drug-release material is abiodegradable polymer, including a poly(lactic-co-glycolic acid). 13.The method of claim 1, wherein injecting drug-release material throughthe delivery wire comprises injecting drug-release material through abore in the delivery wire.
 14. The method of claim 1, wherein injectingdrug-release material through the delivery wire further compriseshydrodissecting a space between a first tissue layer and a second tissuelayer using the drug-release material to create a lake of thedrug-release material near the distal end of the implant, wherein thelake is in fluid communication with the suprachoroidal space.